Syringe assembly for storing and mixing two components

ABSTRACT

The invention relates to syringes for storing and mixing components.

TECHNOLOGICAL FIELD

The presently disclosed subject matter relates to syringes for storingcomponents and mixing them prior to their withdrawal from the syringe,e.g. for the administration of the mixture.

BACKGROUND

More particularly, the presently disclosed subject matter relates tosyringes, in which two components are stored separately within a syringecontainer until they are mixed together therein to form a mixture readyfor use. Often these components are in the form of an activator solutionand an activatable solution, i.e. a solution that is capable of beingactivated by the activator.

U.S. Pat. No. 5,360,410 discloses a safety syringe for mixing a liquidsolute and a drug substance stored in corresponding two compartments ofthe syringe separated by a stopper, which when dislodged from its place,allows the liquid solute from one compartment to inundate the drugsubstance in the other compartment.

US 2014/0058319A1 discloses a syringe for mixing substances stored incorresponding two compartments separated by a tearable membrane, whichis torn when pulled by a lead wire or line that is attached to aremovable outer sleeve or cap.

U.S. Pat. No. 3,785,379 also discloses the use of a membrane andpiercing element disposed within a syringe for administration of mixedliquid and dry substance, wherein the dry substance and liquid areseparably maintained in sealed relation one from the other until themembrane is pierced by the piercing element allowing the substances tobe mixed.

US 2014/0124534 discloses a multi-compartment syringe apparatus forin-situ mixing of a plurality of products before use, wherein thecompartments are of approximately the same volume and are separated by aone-way filter allowing passage of content only from the firstcompartment to the second compartment.

U.S. Pat. No. 4,116,240 discloses a mixing syringe comprising acontainer having a first compartment, a piston, a piston head having asecond compartment, and a wall therebetween, and a plunger, wherein onematerial such as a liquid is stored in the compartment of the syringecontainer and another material such as a powder is stored in thecompartment of the piston head. The wall is configured to be displacedby differential pressure during movement of the piston or by movement ofthe plunger.

U.S. Pat. No. 3,477,432 discloses a mixing syringe with an outer liquidretaining compartment, an inner liquid retaining compartment and abreakable seal therebetween, wherein breaking of the seal allows thecontents of the compartments to be mixed.

U.S. Pat. No. 3,741,383 discloses a container comprising a firstcompartment for storing a liquid material; and a second compartment forstoring a non-liquid material. One of the compartments is surrounded bythe other compartment and is separated therefrom by a wall formed of atwo-layer laminate. One layer of the laminate which is in contact withthe liquid material is impervious to the liquid but penetrable. Theinner layer of that laminate is rigid but soluble in the liquid, suchthat when the insoluble layer is pierced, the soluble layer comes intocontact with the liquid and can thereupon be mixed with the liquid.

U.S. Pat. No. 4,676,775 discloses a fluid administration apparatuscomprising a receptacle for storing fluid and a fluid administrationconduit assembly having a hollow fluid administration tube, a handle anda hollow spike unit extending axially outwardly from the handle. Thereceptacle comprises two fluid chambers separated by a pierceablemembrane. Piercing the membrane by the spike facilitates the mixing ofthe fluids from the two chambers.

GENERAL DESCRIPTION

According to one aspect of the presently disclosed subject matter, thereis provided a syringe assembly for mixing a first and a secondcomponents, comprising prior to its use:

-   -   a syringe container having a proximal end, a distal end, a        cavity extending therebetween along a longitudinal axis, and an        outlet at the distal end in fluid communication with the cavity;    -   a receptacle disposed within the cavity at a location spaced        from the distal end of the container, the receptacle containing        the first component;    -   a ruptureable membrane constituting at least a part of the        receptacle and sealingly separating the receptacle from an        operative portion of the cavity, the operative portion is        disposed between the membrane and the distal end of the        container, the operative portion containing the second        component;    -   a punching and mixing device disposed inside the operative        portion of the cavity and comprising:        -   a punching tip facing the membrane for piercing it when the            punching tip is moved into its punching position in the            direction away from the distal end of the container, thereby            rupturing the membrane to release the first component into            the operative portion of the cavity, the released first            component and the second component constituting a content of            the operative portion of the cavity;        -   a mixing stirrer disposed between the punching tip and the            distal end of the container and capable of stirring the            content of the operative portion of the cavity, when being            moved along the longitudinal axis at least in one direction,            to facilitate the mixing of the first and second components;            and    -   a manipulation arrangement for manipulating the punching and        mixing device to move the punching tip into its punching        position and to move the mixing stirrer at least along the        longitudinal axis at least in one direction, the manipulation        arrangement being configured for being disassembled from the        syringe container from the syringe.

The above structure of the syringe assembly and, particularly, the factthat it includes the mixing stirrer movable along the longitudinal axis,allows homogeneous mixing of the first and second components with areduced risk of generating a foam during the mixing, which can beparticularly advantageous when the components have a relatively highviscosity.

In addition, the above described mutual disposition of the mixingstirrer and the punching tip relative to the ruptureable membrane of thereceptacle and the operative portion of the cavity, allows the componentdisposed within the receptacle, when released therefrom, to move intothe operative portion of the cavity towards the mixing stirrer, therebyfurther facilitating the mixing.

The stirrer can be movable in two directions along the axis and/or berotatable about the longitudinal axis, to facilitate the stirring.

The manipulation arrangement can comprise a shaft, the shaft extendingalong the axis and via said outlet between a shaft distal end disposedoutside the syringe container and configured for applying thereto amanipulating movement, and a shaft proximal end on which the punchingand mixing device is fixed inside the operative cavity. This arrangementallows simultaneous movement of the punching tip and the mixing stirrer,reducing the time needed for the beginning of the mixing.

The shaft can be movable by the manipulation arrangement between anoutermost position of the shaft, in which the shaft projects outwardlyfrom the outlet of the container to a first extent, and an innermostposition of the shaft, in which the shaft projects outwardly from theoutlet of the container to a second extent smaller than the firstextent. For this purpose, the manipulation arrangement can comprise anactuator connected to the distal portion of the shaft for applying anaxial pressing force thereto, it moves the shaft into its innermostposition and releasing the force to allow the shaft to return into itsinitial outermost position.

The manipulation arrangement can be configured for being separated fromthe syringe container, thereby allowing the withdrawal of the mixturefrom the outlet of the container. This can be achieved, for example, byforming the distal end of the container with a distal end surface, andallowing the punching and mixing device to be detachable from at leastthe proximal end of the shaft when the shaft is moved outwardly from thecontainer through the outlet with the mixing stirrer abutting the distalend surface. In this case, fluid communication should be maintainedbetween the cavity and the outlet of the container, which can beprovided by means of a channel formed in the mixing stirrer. Thisarrangement allows withdrawing the mixture from the syringe containeroutlet without the necessity of removing the punching and mixing devicetherefrom.

The punching and mixing device can have a sleeve extending distally fromthe mixing stirrer and configured to receive therein a portion of theshaft associated with its proximal end. The sleeve can be in fluidcommunication with the operative cavity, via a corresponding channel inthe mixing stirrer. The sleeve can have an outer diameter smaller thanthat of the outlet. This arrangement allows using the sleeve forwithdrawing the mixture of the two components from the syringecontainer, when the manipulation arrangement has been dissembledtherefrom.

The manipulation arrangement can comprise an actuator connected to thedistal portion of the shaft for applying an axial pressing force theretoto move the shaft towards and into its innermost position and releasingthe force to allow the shaft to return towards and into its initialoutermost position. The actuator can be provided with a removableactuator safety catch, to prevent the actuator from applying the axialpressing force to the distal portion of the shaft until the catch isremoved.

When the syringe container is to be used for administration the mixtureof the two components, after the manipulation device has been dissembledtherefrom, the container can have an opening at its proximal end, andthe assembly can comprise a plunger passing through the opening so as tobe movable along the longitudinal axis, the plunger having a plungerdistal end sealingly received within the container, and a plungerproximal end disposed outside the cavity so as to allow applying to theproximal end a plunger moving axial force.

The plunger can be provided with a removable safety stopper disposedbetween the plunger proximal end and the opening to prevent the plungerfrom its movement inwardly with respect to the container until thestopper is removed.

The receptacle can constitute, or be attached to, or be disposed within,the distal end of the plunger.

In accordance with another aspect of the presently disclosed subjectmatter, a kit for use with a receptacle containing a first component andcomprising a ruptureable membrane constituting at least a part of thereceptacle, for assembling a syringe for mixing the first component witha second component, the kit comprising:

-   -   a syringe container having a proximal end and a distal end and a        cavity extending therebetween along a longitudinal axis, the        cavity being configured for:        -   receiving therein the receptacle within the cavity closer to            the proximal end of the container than to its distal end, so            that the membrane sealingly separates the receptacle from            the operative portion of the cavity disposed between the            receptacle and the distal end of the container; and        -   receiving in the operative portion of the cavity the second            component;    -   a punching and mixing device configured for being mounted inside        the operative portion of the cavity and comprising:        -   a punching tip configured for piercing the membrane when the            punching tip is facing it and moved into its punching            position in the direction away from the distal end of the            container, thereby rupturing the membrane to release the            first component into the operative portion of the cavity,            the released first component and the second component            constituting a content of the operative portion of the            cavity;        -   a mixing stirrer disposed between the punching tip and the            distal end of the container and capable of stirring the            content of the operative portion of the cavity, when being            moved along the longitudinal axis at least in one direction,            to facilitate the mixing of the first and second components;            and    -   a manipulation arrangement for manipulating the punching and        mixing device to move the punching tip into its punching        position and to move the mixing stirrer at least along the        longitudinal axis at least in one direction.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to better understand the subject matter that is disclosedherein and to exemplify how it may be carried out in practice,embodiments will now be described, by way of non-limiting example only,with reference to the accompanying drawings, in which:

FIG. 1 is a perspective view of a syringe assembly according to oneembodiment of the presently disclosed subject matter;

FIG. 2 is a perspective view of a punching and mixing unit of thesyringe assembly shown in FIG. 1, including a punching and mixingdevice, a manipulation arrangement and a receptacle;

FIG. 3A is an enlarged cross-sectional view of a receptacle of thesyringe assembly shown in FIG. 1;

FIG. 3B is an enlarged perspective view of the punching and mixingdevice shown in FIG. 2;

FIG. 3C is an enlarged cross-sectional view of a manipulation head ofthe manipulation arrangement shown in FIG. 2, including a rod whosedistal end is in the form of a sleeve;

FIG. 3D is an enlarged perspective view of the sleeve shown in FIG. 3C;

FIGS. 4A to 4D illustrate the manner, in which mixing is performed inthe syringe assembly shown in FIG. 1; and

FIGS. 5A to 5C illustrate the manner, in which the syringe assemblyshown in FIGS. 4A to 4D is brought into a state, in which its contentscan be administered;

FIGS. 6A and 6B illustrate the manner in which administration can beperformed using the syringe assembly shown in FIG. 5C;

FIG. 7 is a schematic cross-sectional view of a portion of the syringeassembly shown in FIG. 3B, taken along a plane VII-VII;

FIG. 8 illustrates a kit comprising components, from which an assemblyof the kind shown in FIG. 1, can be assembled.

DETAILED DESCRIPTION OF EMBODIMENTS

FIGS. 1 to 3C illustrate a syringe assembly generally designated as 1,for mixing two components to produce a homogeneous mixture. Thecomponents can be of the kind, which once mixed, produce a curablesubstance, in which case a first component can be capable of beingactivated by the second component. Once the desired mixture or substanceis produced, the syringe assembly is to be used for its administrationas required. Thus, the syringe assembly 1 has an initial state (prior tomixing the two components), a mixing state (in which mixing the twocomponents is performed), and an administration state (in which thesyringe assembly is ready for the administration of the substanceproduced by the mixture of the two components).

With reference to FIGS. 1 to 3A, the syringe assembly 1 in its initialstate comprises:

-   -   a syringe container 10 having an open proximal end 11, a distal        end 12 with an outlet 14 surrounded by a distal end surface 16,        and a syringe cavity 15 extending between the two ends along a        longitudinal axis A;    -   a plunger 17 partially received within the syringe cavity 15 via        the open end 11 and having a plunger distal end 17 a disposed        within the cavity 15 and a plunger proximal end 17 b disposed        outside the cavity, the plunger being movable from an initial        position at the initial state of the assembly, in which the        plunger distal end 17 a is disposed adjacent the proximal end 11        of the container 10, and a final position, in which the plunger        distal end 17 a is spaced from the proximal end 11 of the        container 10 to a maximal extent at the administration state of        the assembly;    -   a receptacle 20 having a receptacle cavity 21 (FIG. 3A)        accommodating the first component, and disposed within the        syringe cavity 15 adjacent and/or in the plunger distal end 17 a        so that a cavity operative portion 13 is created in the syringe        cavity 15 between an area 30 of the receptacle 20 facing towards        the distal end 12, and the outlet 14 of the syringe container,        where the second component is accommodated;    -   a movable punching and mixing device 40 (FIG. 2) disposed inside        the operative portion of the cavity and comprising a punching        tip 41 facing the receptacle 20 for piercing it to release the        first component into the operative portion of the cavity, and a        mixing stirrer 43 disposed between the punching tip and the        distal end 12 of the container 10 for stirring the content of        the operative portion of the cavity; and    -   a manipulation arrangement 50 detachably attached to the        punching and mixing device 40, constituting therewith a punching        and mixing unit shown separately in FIG. 2, for manipulating the        punching and mixing device 40 in the mixing state of the        assembly, and for being dissembled from the punching and mixing        device 40 and from the syringe container 10, to bring it into        the administration state.

The entire receptacle 20 or its area 30 or only a portion of this areais made of a ruptureable material capable of being plastically deformedat least at that area, e.g. being broken, torn, disrupted or penetratedso as to provide access therethrough to the interior of the receptacle.The area 30 thus constitutes a membrane, which can be ruptured from thedirection of the operative portion 13 of the syringe cavity and therebycreate a fluid communication between the receptacle cavity 21 and theoperative portion 13. The membrane 30 can be a pre-tensioned membrane.Typically, once ruptured the tensioned membrane will retract towards itscircumference, thereby widening the ruptured area. The receptacle 20 canbe configured to maintain its integrity at areas other than the rupturedarea of the membrane 30. Alternatively, the receptacle 20 can beconfigured to collapse when ruptured, as long as this does not interferewith the release of the first component into the operative portion ofthe cavity.

The receptacle cavity 21 can have a shape facilitating the release ofthe first component therefrom once the membrane 30 is ruptured. Forexample, this can be a semispherical shape as shown in FIG. 3A.

The receptacle can be configured to be sealingly received within thesyringe cavity 15 for preventing fluid communication between the cavityoperative portion 13 and the open proximal end 11 of the container. Suchsealing can be provided by any suitable known means such as e.g. one ormore O-rings 18 (FIG. 3A) mounted on the circumference of the receptacle20 and holding it firmly in place within the syringe cavity 15.Alternatively, or in addition, a sealing can be provided at the plungerdistal end 17 a received within the syringe cavity 15. The receptacle 20can be attached to or mounted in the plunger distal end 17 a.

The plunger 17 can further be provided with a removable safety stopper19 disposed between the plunger proximal end 17 b and the syringeproximal end 11 to prevent the plunger from its occasional movementinwardly into the syringe cavity 15 until the stopper is removed.

The punching tip 41 and the mixing stirrer 43 of the punching and mixingdevice 40 are held at fixed distance from each other by a common rod 60.

This distance can be in the range of 0.25 to 0.75 of the length of thesyringe cavity 15. As best seen FIG. 3B, in the described example, thepunching tip 41, the mixing stirrer 43 and the rod 60 are all producedas a unitary body as shown in FIG. 2, made of a rigid material such asplastic. Alternatively, these elements can be produced separately andassembled to form the punching and mixing device 40. In addition oralternatively, the elements can be made of different materialscorresponding to their functions. For example, the mixing stirrer 43 canbe made of a semi-rigid material in order to reduce foaming duringmixing the punching tip 41 can at least partially be made of a rigidmaterial.

The punching tip 41 (FIG. 3B) has a proximal sharp apex 48 configuredfor punching the membrane 30, a distal wide skirt 49, and a tip body 47extending therebetween. The tip body 47 can have a shape complementaryto that of the receptacle cavity 21 (not shown), so as to facilitate therelease of the contents of the receptacle towards the operative portion13 of the cavity. The skirt 49 can have a flexible edge 49 a, e.g. dueto the skirt's circumference being thinner than its central area,allowing thereby the skirt's edge to change its orientation whencontacting the membrane 30, to further facilitate the release of thecontent of the receptacle into the operative portion 13 of the cavityduring the mixing operation. The sharp apex 48 and, optionally, the tipbody 47 of the punching tip 48 can be made of a rigid material, whilstthe distal wide skirt 49 can be made of a flexible material.

The mixing stirrer 43 has such a form as to allow fluid such as thefirst and second components or their mixture, to pass through and/oraround the stirrer, when it is moved axially and, optionally, when it isrotated. In a described example, the stirrer is in the form of a rotorand a plurality of curved angled blades 43 a spaced from each other bypassages 43 b. Alternatively, the blades can be straight and have planarsurfaces and/or they may not be angled. In another example, the mixingstirrer can be in the form of a disc with a pattern of holes or slots.

The rod 60 (FIG. 3B) has a hub section 61 surrounded by the mixingstirrer 43, a rod proximal section 63 extending between the punching tip41 and the mixing stirrer 43, and a rod distal section 64 (FIG. 3C)projecting distally from the mixing stirrer 43. The rod distal section64 has the form of a hollow sleeve terminating at a sleeve outlet 62(FIG. 3D), which is in fluid communication with the operative portion 13of the syringe cavity. One possible manner, in which such fluidcommunication can be provided is a channel 65 (FIG. 3B) in the hubsection 61 connecting an opening 66 made in the hub, with the hollowinterior of the sleeve 64.

With reference to FIGS. 1, 2 and 3C, the manipulation arrangement 50comprises a manipulation head 46 and a shaft 45 having a shaft distalend 45 a received within the manipulation head 46 and a shaft proximalend 45 b tightly received within the rod distal section 64. Themanipulation head 46 is configured for moving the shaft 45 and,consequently, the punching and mixing device 40, along the longitudinalaxis A and, optionally, rotating it about the longitudinal axis A.

The manipulation head 46 comprises an actuator 52 for applying to theshaft an axial pressing force, to move the shaft 45 with the rod distalsection 64 into their innermost position with respect to the cavityoperative portion 13 of the syringe cavity 15, in which the punching tip41 is pressed into the area 30 of the receptacle 20, and for releasingthe force to allow the shaft to return, into its initial position. Theactuator 52 can allow moving the shaft with the rod distal section intoany intermediate position between their innermost and initial positions,by applying a reduced pressing force or limiting the releasing force,respectively. In the described example, the actuator 52 is in the formof a springed button 53 having a stem 55 received within themanipulation head 46 and connected to or integrally formed with theshaft distal end 45 a.

The manipulation arrangement 50 can further comprise a removableactuator safety catch 54 (FIG. 4A), to prevent the actuator 52 fromapplying the axial pressing force to the shaft 45 until the stopper isremoved.

The manipulation head 46 with the shaft 45 can be rotated manually orautomatically (not shown).

The above described elements of the syringe assembly 1 have thefollowing dimensions:

Dc—diameter of the operative cavity 13;

Lc—axial length of the operative cavity in the initial state of thesyringe assembly, which is defined by a distance between the membrane 30and the distal end 12 of the syringe container;

Do—diameter of the outlet 14;

D_(sh)—diameter of the shaft 45;

D_(s)—outer diameter of the sleeve 64, which is either smaller than thediameter Do of the outlet 14 such as to allow the sleeve to pass freelythrough the outlet 14 (in case the sleeve has a length that does notexceed the distance between the hub 61 of the mixing stirrer 43 and thedistal end surface 16 of the syringe container so that it is fullyaccommodated within the operative cavity 13 in the initial state of thesyringe assembly), or which essentially equals the diameter Do of theoutlet 14 so as to allow the sleeve 64 to be tightly received within theoutlet 14 (in case the sleeve has a length that is greater than thedistance between the hub 61 of the mixing stirrer 43 and the distal endsurface 16 of the syringe container so that it protrudes distally fromthe outlet 14 in the initial state of the syringe assembly);

d_(s)—inner diameter of the sleeve 64, which essentially equals thediameter D_(sh) of the shaft 45, so as to ensure that a portion of theshaft including its distal end 45 a is tightly received within thesleeve 64;

D_(m)—maximal diameter of the mixing stirrer 43, which is in the range0.25 Dc≦Dm<Dc. For example, the range can be 0.5 Dc≦Dm≦0.95 Dc, and moreparticularly 0.7 Dc≦Dm≦0.9 Dc.

In the above description, all the diameters are meant to be measured ina plane perpendicular to the axis A of the syringe assembly and, if inthat plane the shape of an element to which the diameter refers, is notcircular, the diameter should be considered as being that of a circleinscribed in such an element. For example, if the operative cavity 13 isnot circular in its cross-sectional plane taken perpendicular to theaxis A, its diameter Dc is that of a circle inscribed in the operativecavity in such a plane.

With reference to FIGS. 4A to 4D, in order to have the first and secondcomponents mixed in the syringe assembly as described above, thefollowing steps are to be performed:

-   (a) the actuator safety catch 54 is removed to allow pressing the    springed button 53 of the actuator 52 (FIG. 4A);-   (b) the springed button 53 of the actuator 52 is pressed, thereby    applying axial force to the shaft 45 and moving it together with the    punching and mixing device 40, along the longitudinal axis A into    their innermost position with respect to the operation portion 13 of    the syringe cavity 15, in which the punching tip 41 is pressed into    the membrane 30 of the receptacle 20 and the membrane 30 is    ruptured; this results in the release of the first component    disposed in the receptacle cavity 21 (FIGS. 4B and 4C).-   (c) releasing the button 53, thereby allowing the shaft 45 to return    to its initial position;-   (d) pressing and releasing the button 53 again as many times as    needed to facilitate the mixing of the two components (FIG. 4D); and-   (e) optionally, rotating the manipulation head 46 about the    longitudinal axis A, thereby rotating the punching and mixing device    40, to further facilitate the mixing (FIG. 4D).

Once the two components have been mixed, the syringe assembly can bebrought into its administration state by the following steps illustratedin FIGS. 5A to 5C:

-   -   (i) pulling the manipulation arrangement 50 with the punching        and mixing device 40 in the distal direction until the mixing        stirrer 43 abuts the distal end surface 16 of the syringe        container (FIG. 5A); in this position the sleeve 64 projects to        a maximal extent from the outlet 14 of the syringe container;    -   (ii) continuing pulling the manipulation arrangement 50 until        the shaft 45 is removed out of the sleeve 64 (FIG. 5B); and    -   (iii) removing the plunger safety stopper 19 to allow the        plunger 17 to move inwardly into the syringe cavity 15.

In this position, the syringe assembly is in its administration state(FIG. 6A), and its content can be administered through the outlet 62 ofthe sleeve 64, which is in fluid communication with the syringe cavity15 via the channel 65 in the hub of the mixing stirrer 43, by the axialmovement of the plunger in the distal direction until the receptaclemembrane 30 or its remainder abuts the punching and mixing device 40(FIG. 6B).

In an alternative embodiment of the syringe assembly according to thepresently disclosed subject matter, the punching and mixing device 40can be formed without the sleeve 64 but rather it can be held directlyby the shaft 45, whose proximal end 45 b can be received within the hub61 of the mixing stirrer 43, in which case the channel 65 will providefluid communication between the syringe cavity 15 and the outlet 14 ofthe syringe container and its content will be administered therethrough.In such embodiment, the outlet 14 can extend distally from the distalend 12 of the syringe container to any desired extent. In addition, theoutlet 14 of the syringe container 10 can be provided with a sealingpierced septum 63, as shown in FIG. 3D, to prevent occasional exposureof the contents of the syringe assembly to its exterior. The piercedseptum 63 can be made of an elastic material such as, for example,silicone. An administration element can be mounted on the outlet 14.

It needs to be noted that in this embodiment it is important to ensurethat the punching and mixing device 40 does not change its orientationinside the cavity 15 when it detaches from the shaft 45 to bring thesyringe assembly into its administration state, because such change oforientation can prevent the plunger 17 from taking its desired distalposition for administration of the content of the syringe assembly.

With reference to FIG. 7, the above change of orientation can beprevented by designing the mixing stirrer so that its parameters meetthe following three conditions:

L>D_(c);

D_(m)<D_(c); and

H≧√{square root over (L ² −D _(m) ²)}=√{square root over (L ² −D _(c)²)};

where:

L is diagonal extension of the mixing stirrer 43 in its cross-sectionalong a plane passing through its maximal diameter and including theaxis A;

D_(c) is diameter of the operative cavity 13;

D_(m) is maximal diameter of the mixing stirrer 43; and

H is maximal extension of the mixing stirrer along the axis A.

For example, for a syringe assembly with D_(c)=15.8 mm and D_(m) almostequal to D_(c), L can be chosen to be L=16 mm and H can be not less than2.5 mm. In case, D_(m)=15.4 mm, the extension Hof the stirrer 43 is notless than 4.3 mm.

According to another aspect of the presently disclosed subject matter,there can be provided a kit for assembling a syringe for mixing thefirst component with the second component, which can comprise all or apart of the elements of the syringe assembly 1 described above. Oneexample of such kit 1′ is shown in FIG. 8, and it comprises a syringecontainer 10′, a plunger 17′, a receptacle 20′ with a ruptureablemembrane 30′ separate from or as an integral unit with the plunger 17′containing the first component, a punching and mixing device 40′ with orwithout a sleeve 64′, a manipulation arrangement 50′ and a package withthe second component, all similar to the respective elements describedabove.

The above described syringe assemblies are designed so that a volume Vof the operative portion 13 of the cavity is greater than a volume vwithin which the second component is disposed in the receptacle 20. In aparticular design, their ratio V:v can be in the range of 10 to 200.

The above described syringe assemblies can particularly be used inapplications where the second component is chemically inactive and thefirst component is an activator for the second component.

For example, the first component can be calcium chloride and the secondcomponent can be, for example, Prothrombin-Proconvertin-StuartFactor-Antihemophilic Factor B (PPSB) and fibrinogen stabilized bysodium citrate, in which case, upon mixing the two components in thesyringe assembly, the PPSB zymogens will become activated.

In a further example, the first component can be anti-sense DNAcomplementary to a thrombin binding aptamer, and the second componentcan be thrombin stabilized by a thrombin binding aptamer which preventsautocatalysis. Upon mixing the two components in the syringe assembly,the activity of the thrombin would be restored.

In a still further example, the first component can be an agent whichactivates fibrinogen, such as, for example, thrombin or a substanceobtainable from snake venom at low activity/concentration and the secondcomponent can be fibrinogen/BAC2. Upon mixing the two components in thesyringe assembly, the thrombin would enzymatically act on the fibrinogento form fibrin. At lowest levels of thrombin, for example, 1 U, thefibrin polymerization time will be relatively slow, i.e., minutes,allowing the activated BAC2 to be delivered for hemostasis, sealing ortissue adhesion applications.

For embodiments wherein the first component comprises thrombin and thesecond component comprises fibrinogen, one or both of the components canoptionally be prepared from an initial blood composition. The bloodcomposition can be whole blood or blood fractions, i.e. a fraction ofwhole blood such as plasma. The origin of the fibrinogen and thrombincan be autologous whereby they would be manufactured from the patient'sown blood or from pooled blood or blood fractions. It is also possiblethat the components are prepared by recombinant methods.

In one embodiment of the invention, the fibrinogen component comprises abiologically active component (BAC) which is a solution of proteinsderived from blood plasma, optionally further comprising antifibrinolytic agents such as tranexamic acid and/or stabilizers such asarginine, lysine, pharmaceutically acceptable salts thereof, or mixturesthereof. BAC is optionally derived from cryoprecipitate, in particularconcentrated cryoprecipitate. The term “cryoprecipitate” refers to ablood component which is obtained from frozen plasma prepared from wholeblood, recovered plasma or from source plasma which is collected byplasmapheresis. A cryoprecipitate is optionally obtained when frozenplasma is slowly thawed in the cold, typically at a temperature of 0-4°C., resulting in the formation of precipitate that contains fibrinogenand factor XIII. The precipitate can be collected, for example, bycentrifugation and dissolved in a suitable buffer such as a buffercontaining 120 mM sodium chloride, 10 mM trisodium citrate, 120 mMglycine, 95 mM arginine hydrochloride, 1 mM calcium chloride. Thesolution of BAC optionally comprises additional factors such as forexample Factor VIII, Factor XIII, fibronectin, von Willebrand factor(vWF), vitronectin, etc. for example as described in U.S. Pat. No.6,121,232 and WO9833533. The composition of BAC optionally comprisesstabilizers such as tranexamic acid and arginine hydrochloride. Theamount of tranexamic acid in the solution of BAC is optionally in therange of from about 80 to about 110 mg/ml. The amount of argininehydrochloride is optionally in the range of from about 15 to about 25mg/ml.

Optionally, the solution is buffered to a physiological compatible pHvalue. The buffer can comprise glycine, sodium citrate, sodium chloride,calcium chloride and water for injection as a vehicle. Glycine isoptionally present in the composition at a concentration in the range offrom about 6 to about 10 mg/ml; sodium citrate is optionally present ata concentration in the range of from about 1 to about 5 mg/ml; sodiumchloride is optionally present at a concentration in the range of fromabout 5 to about 9 mg/ml; and calcium chloride is optionally present ata concentration in the range of from about 0.1 to about 0.2 mg/ml.

In one embodiment of the invention, the fibrinogen component is derivedfrom blood. In some other embodiments, BAC is a biologically activecomponent that does not contain tranexamic acid. This is considered asecond generation BAC and is referred to in the art as BAC2. In anotherembodiment of the invention, the concentration of plasminogen and/orplasmin in the blood derived component comprising fibrinogen is lowered.The removal of plasmin and plasminogen from the blood derived componentcan be carried out as described in U.S. Pat. No. 7,125,569 andWO02095019.

The thrombin component optionally comprises calcium chloride, humanalbumin, mannitol, sodium acetate and water for injection.

1. A syringe assembly for mixing a first and a second components,comprising prior to its use: a syringe container having a proximal end,a distal end, a syringe cavity extending therebetween along alongitudinal axis (A), and an outlet at the distal end in fluidcommunication with the syringe cavity; a receptacle disposed within thesyringe cavity at a location spaced from the distal end of thecontainer, the receptacle containing the first component; a ruptureablemembrane constituting at least a part of the receptacle and sealinglyseparating the receptacle from an operative portion of the syringecavity, the operative portion is disposed between the membrane and thedistal end of the syringe container, the operative portion containingthe second component; a punching and mixing device disposed inside theoperative portion of the syringe cavity and comprising: a punching tipfacing the membrane for piercing it when the punching tip is moved intoits punching position in the direction away from the distal end of thecontainer, thereby allowing rupturing the membrane to release the firstcomponent into the operative portion of the syringe cavity, the releasedfirst component and the second component constituting of a mixture; amixing stirrer disposed between the punching tip and the distal end ofthe container and capable of stirring the content of the operativeportion of the syringe cavity, when being moved along the longitudinalaxis at least in one direction, to facilitate the mixing of the firstand second components; and a manipulation arrangement for manipulatingthe punching and mixing device to move the punching tip into itspunching position and to move the mixing stirrer at least along thelongitudinal axis at least in one direction.
 2. A syringe assemblyaccording to claim 1, wherein the mixing stirrer is movable in twodirections along the axis to perform the stirring and/or wherein themixing stirrer is rotatable about the longitudinal axis.
 3. A syringeassembly according to claim 1, wherein the manipulation arrangement isconfigured for being separated from the syringe container, therebyallowing the withdrawal of the mixture from the outlet of the container.4. A syringe assembly according to claim 1, wherein the manipulationarrangement comprises a shaft, the shaft extending along the axis andvia said outlet between a shaft distal end disposed outside the syringecontainer and configured for applying thereto a manipulating movement,and a shaft proximal end on which the punching and mixing device isfixed inside the operative portion of the syringe cavity, optionally,wherein the shaft is movable by the manipulation arrangement between anoutermost position of the shaft, in which the shaft projects outwardlyfrom the outlet of the container to a first extent, and an innermostposition of the shaft, in which the shaft projects outwardly from theoutlet of the container to a second extent smaller than the firstextent.
 5. A syringe assembly according to claim 4, wherein the distalend of the container is formed with a distal end surface, and thepunching and mixing device is detachable from at least the proximal endof the shaft when the shaft is moved outwardly from the containerthrough the outlet with the mixing stirrer abutting the distal endsurface, and wherein fluid communication is maintained between thesyringe cavity and the outlet of the container, and optionally, whereinthe fluid communication is maintained between the syringe cavity and theoutlet of the container via a corresponding channel in the mixingstirrer.
 6. A syringe assembly according to claim 1, wherein the mixingstirrer has a maximal diameter D_(m) greater than that of the outlet,and optionally, wherein the syringe cavity has a cross-section definedby an inscribed circle having a diameter D_(c) and the extension D_(m)equals at least 0.25 D_(c).
 7. A syringe assembly according to claim 1,wherein the mixing stirrer has parameters that meet the following threeconditions:L>D_(c);D_(m)<D_(c); andH≧√{square root over (L ² −D _(m) ²)}=√{square root over (L ² −D _(c)²)}; where: L is diagonal extension of the mixing stirrer in itscross-section along a plane passing through its maximal diameter andincluding the axis A; D_(c) is diameter of the operative portion of thesyringe cavity; D_(m) is maximal diameter of the mixing stirrer; and His maximal extension of the mixing stirrer along the axis A.
 8. Asyringe assembly according to claim 4, wherein the punching and mixingdevice comprises a sleeve extending distally from the mixing stirrer andconfigured to receive therein a portion of the shaft associated with itsproximal end.
 9. A syringe assembly according to claim 8, wherein thesleeve is in fluid communication with the syringe cavity, via thecorresponding channel in the mixing stirrer.
 10. A syringe assemblyaccording to claim 8, wherein the punching tip, the mixing stirrer, theinterior portion of the shaft and the sleeve are formed as a unitarybody.
 11. A syringe assembly according to claim 8, wherein the sleevehas an outer diameter smaller than that of the outlet.
 12. A syringeassembly according to claim 1, wherein the receptacle has an innercavity covered by the membrane and containing the second component sothat, when the membrane is ruptured by the punching tip, the secondcomponent can exit the inner cavity only through the rupture in themembrane.
 13. A syringe assembly according to claim 1, wherein thepunching tip has a body terminating at a sharp apex and divergingtherefrom to a wide distal portion of the body.
 14. A syringe assemblyaccording to claim 1, wherein the syringe assembly comprises a flexiblepierced septum disposed on the outlet of the container, and sealing thesyringe cavity.
 15. A syringe assembly according to claim 4, wherein themanipulation arrangement comprises an actuator connected to the distalportion of the shaft for applying an axial pressing force thereto tomove the shaft towards and into its innermost position and releasing theforce to allow the shaft to return towards and into its initialoutermost position, and optionally, wherein the assembly furthercomprises a removable actuator safety catch, to prevent the actuatorfrom applying the axial pressing force to the distal portion of theshaft until the catch is removed.
 16. A syringe assembly according toclaim 1, wherein the container has an opening at its proximal end, andthe assembly further comprises a plunger passing through the opening soas to be movable along the longitudinal axis, the plunger having aplunger distal end sealingly received within the container, and aplunger proximal end disposed outside the syringe cavity so as to allowapplying to the proximal end a plunger moving axial force, andoptionally, wherein the assembly further comprises a removable safetystopper disposed between the plunger proximal end and the proximalopening of the container to prevent the plunger from its movementinwardly with respect to the container until the stopper is removed. 17.A syringe assembly according to claim 16, wherein the receptacleconstitutes the distal end of the plunger.
 18. A syringe assemblyaccording to claim 1, wherein the second component is chemicallyinactive and the first component is an activator for the secondcomponent.
 19. A syringe assembly according to claim 1, wherein a volumeV of the operative portion of the syringe cavity is greater than avolume v within which the second component is disposed in thereceptacle, particularly their ratio V:v is in the range of 10 to 200.20. A kit for use with a receptacle containing a first component andcomprising a ruptureable membrane constituting at least a part of thereceptacle, for assembling a syringe for mixing the first component witha second component, the kit comprising: a syringe container having aproximal end and a distal end and a syringe cavity extendingtherebetween along a longitudinal axis (A), the syringe cavity beingconfigured for: receiving therein the receptacle within the syringecavity closer to the proximal end of the container than to its distalend, so that the membrane sealingly separates the receptacle from anoperative portion of the syringe cavity disposed between the receptacleand the distal end of the container; and receiving in the operativeportion of the syringe cavity the second component; a punching andmixing device configured for being mounted inside the operative portionof the syringe cavity and comprising: a punching tip configured forpiercing the membrane when the punching tip is facing it and moved intoits punching position in the direction away from the distal end of thecontainer, thereby rupturing the membrane to release the first componentinto the operative portion of the syringe cavity, the released firstcomponent and the second component constituting a mixture in theoperative portion of the syringe cavity; a mixing stirrer disposedbetween the punching tip and the distal end of the container and capableof stirring the content of the operative portion of the syringe cavity,when being moved along the longitudinal axis at least in one direction,to facilitate the mixing of the first and second components; and amanipulation arrangement for manipulating the punching and mixing deviceto move the punching tip into its punching position and to move themixing stirrer at least along the longitudinal axis at least in onedirection.